Adaptive immune responses associated with the progression of premalignant lesions to colorectal cancer

Immune response during the progression of premalignant lesions and their molecular subtype to colorectal cancer (CRC) remains unclear. Using gene expression data from 135 normal (NLs), 176 conventional adenomas (AD), 42 serrated polyps (SER), and 2760 CRC samples, we estimated overall immune activity (ImmuneScore) and tumor-infiltrating lymphocyte (TIL) abundance using the xCell tool. We evaluated association of the ImmuneScore and TILs with CRC progression using adjusted multivariable regression models. Immunohistochemistry (IHC) staining for five immunological markers was conducted on NL, early- and late-stage AD, and carcinoma tissues from 75 study participants. The consensus molecular subtypes (CMS) of adenomas and carcinomas were classified using random forest methods, and the association of immune activity with CRC progression was assessed. Immune activity consistently decreased from NLs through premalignant lesions to adenocarcinoma, more prominently in AD than SER (AD vs. NL: odds ratio = 0.86, 95% CI = 0.84‒0.88; SER vs. NL: 0.89, 0.85‒0.93). Similar patterns were observed in B cells, CD4 + effector memory T cells, CD8 + naïve T cells, and CD8 + cytotoxic T cells. IHC staining of these immunological markers verified their roles in CRC progression. Our analysis revealed that CMS3 is a major subtype of AD. Consistently, higher immune activity was observed in premalignant lesions than in CRCs of the CMS3 subtype. This study provides additional insights into alterations in immune response and their important role in CRC premalignant lesion progression and subtypes.